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Mitochondrial CB1 receptors regulate neuronal energy metabolism

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Abstract

The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB1) is present at the membranes of mouse neuronal mitochondria (mtCB1), where it directly controls cellular respiration and energy production. Through activation of mtCB1 receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB1 receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB1 receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein–coupled receptor signaling in the brain.

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Figure 1: CB1 receptors in neuronal mitochondria.
Figure 2: Mt-CB1 is present in both GABAergic and glutamatergic CA1 hippocampal neurons.
Figure 3: Direct regulation of mitochondrial activity by mtCB1 receptors in the brain.
Figure 4: MtCB1 receptors are activated by THC, and mitochondria contain biologically active endocannabinoids.
Figure 5: Hemopressin and HU-biot do not penetrate cells and cannot alter cellular respiration in intact cells.
Figure 6: Intracellular CB1 receptors contribute to depolarization-induced DSI.
Figure 7: Inhibition of mitochondrial activity potentiates DSI.

Change history

  • 27 March 2012

    In the version of this article initially published online, the description of the procedure given in the Online Methods for synthesis of fluorescent hemopressin, taken from a different protocol not used in this work, was incorrect. The entire paragraph has been replaced. The error has been corrected in the PDF and HTML versions of this article.

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Acknowledgements

We thank D. Gonzales, N. Aubailly and all the personnel of the Animal Facility of the NeuroCentre Magendie for mouse care and genotyping; all the members of G.M.'s laboratory for discussions; and A. Bacci, D. Cota, M. Guzman, U. Pagotto, P.V. Piazza and C. Wotjak for critically reading the manuscript. Supported by AVENIR/INSERM (G.M.), INSERM–Agence Nationale de la Recherche (Retour Post-Doc ANR-09RDPOC-006-01 (G.B.), European Union 7th Framework Program (REPROBESITY, HEALTH-F2-2008-223713, G.M. and B.L.), European Research Council (ENDOFOOD, ERC-2010-StG-260515, G.M.), Fondation pour la Recherche Medicale (G.M. and M.M.-L.), Region Aquitaine (G.M.), Fyssen Foundation (E.S.-G.), University of Bordeaux (J.L.), Red de Trastornos Adictivos, Instituto de Salud Carlos III (RD07/0001/2001, P.G.), Basque Country Government (GIC07/70-IT-432-07, P.G.), University of the Basque Country UPV/EHU (UFI11/41, P.G.), Comunidad de Madrid (S2010/BMD-2353, M.L.L.-R.), MICINN (SAF2009-07065, P.G.; SAF2010-22198-C02-01, M.L.L.-R.), Ramon y Cajal program (S.O.-G.), Deutsche Forschungsgemeinschaft (FOR926, B.L.) and CONACyT (E.S.-G.).

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N.P., J.L. and L.B. equally contributed to experiments. P.G. and R.R. equally supervised different parts of this work. G.B., P.G., R.R. and G.M. designed the study. G.B. performed the biochemical experiments. F.M., J.L. and C.M. performed the electrophysiological studies. N.P. performed the anatomical studies. L.B. and E.S.-G. performed in vivo studies and stereotactic injections of viruses. A.D., M.M.-L., E.H.-C. and A.C. participated in biochemical experiments. I.M. measured endocannabinoids and endocannabinoid-degrading enzymatic activities. S.O.-G., M.M.-F. and M.L.L.-R. synthesized and biochemically characterized HU-biot and measured intracellular hemopressin and AM251. J.G. generated fluorescent hemopressin and performed in vitro studies on cell penetration. M.K., S.G. and B.L. provided the viruses for local re-expression of CB1 receptors. F.C. supervised part of the work. P.G. supervised the anatomical studies. R.R. supervised biochemical experiments. G.M. conceived and supervised the whole study and wrote the manuscript. All authors edited the manuscript.

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Correspondence to Giovanni Marsicano.

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The authors declare no competing financial interests.

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Bénard, G., Massa, F., Puente, N. et al. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15, 558–564 (2012). https://doi.org/10.1038/nn.3053

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